Vaptans and hyponatremia in critical patients.

Hyponatremia is the most frequent fluid and electrolyte disorder in hospitalized patients (20%), particularly in ICU, associated with an increase in morbility and mortality. While hypovolaemic hyponatremia needs to be corrected with the replacement of the lost extracellular fluid by isotonic saline, euvolaemic (SIADH) and hypervolaemic hyponatremia (oedematous states like decompensated heart failure, liver cirrhosis, i.e.) are treated by restriction of fluid intake, loop diuretics and hypertonic saline. A novel approach consists in use of vaptans, non-peptide arginine vasopressin (AVP) receptor antagonists. Vaptans cause “aquaresis”, which results in the correction of plasma osmolality and serum sodium levels, without activation of the renin-angiotensin-aldosterone system or changes in blood pressure and renal function. In this paper we critically reviewed the results of the available randomized controlled critical trials, discussing the effectiveness and safety of vaptans in treating hypervolaemic and euvolaemic hyponatremia in critical patients.


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Università degli Studi di Salerno Hypovolaemic hyponatremia simply requires the administration of lost fluids in the form of isotonic saline. As far as euvolaemic and hypervolaemic hyponatremia are concerned, the use of hypertonic saline solution is reserved for severe hyponatremia with neurological symptoms. The correction of the sodium intake should be slow and gradual and not exceed 8-12 mEq/l in the first 24 hours in case of acute hyponatremia, even slower in correcting chronic hyponatraemia (maximum 8 mEq/l in 24 h). Overly rapid correction, in fact, can cause serious and irreversible neurological disorders, such as the pontine myelinolysis due to brain glial damage (oligodendrocytes) (7,8,9,10,11). Osmotic demyelination syndrome results in confusion, behavioral changes, dysphagia, dysarthria, mutism, spastic hemiplegia or quadriplegia, convulsions, coma, death (3).
Other conventional treatments used in managing hyponatremia consist in water restriction and loop diuretics (oedematous states). Lithium and Demeclocycline, capable of correcting hyponatremia causing nephrogenic insipidus diabetes, are rarely used because of their side effects and only under certain conditions (SIADH). Mannitol and urea (12) can be used to induce osmotic diuresis with increased excretion of free water.
Most of these therapies are of moderate efficacy. In any case it is important to monitor blood volume and assess frequently sodium levels (i.e. more a day by ABG), as well as other electrolytes, urine output, renal and cardiovascular function when correcting the serum sodium. None of the conventional therapies directly addresses the effects of elevated vasopressin levels, which is the underlying cause of many cases of hyponatremia. 3 Università degli Studi di Salerno ARGININE VASOPRESSIN AND VAPTANS Arginine Vasopressin or ADH (Antidiuretic hormone) is a cyclic peptide (9 amino-acids) with a disulfide bridge. It is synthesized in the hypothalamus (sopraoptic and paraventricular nuclei) and transported along the axons to the posterior lobe of hypophysis. It is released into the circulation in response to a number of stimuli (13). These stimuli can be osmotic (osmoreceptors situated in the anterior hypothalamus) or non-osmotic (low-pressure baroreceptors, present in large veins, right and left atrium, lungs; high-pressure receptors, present in the carotid sinuses and aortic arch). Other non-osmotic stimuli are hypovolemia, stress, hypoglycemia, nausea and vomiting, drugs. Circulating ADH is metabolized by a vasopressinase (also called oxytocinase or placental leucine aminopeptidase), widely expressed on cellular membrane. Well known ADH receptors are: V1a, V1b (also known as V3), V2. They belong to G-proteincoupled receptor superfamily. V1a and V1b receptors activate the phospholipase C/protein kinase C pathway, while V2 receptor activates the cAMP/protein kinase A pathway.
V1a receptor (expressed on surface of vascular smooth muscle cells, cardiomyocytes, platelets, hepatocytes, brain and muscle uterine cells) regulates vasoconstriction, inotropic effect, platelets aggregation, glycogenolysis, anxiety and stress, myocyte hypertrophy (14). V1b receptor, found in anterior pituitary gland, increases release of ACTH (15). V2 receptor is expressed on endothelial cells, where it determines release of von Willebrand factor, and on the basolateral membrane of the principal cells of the renal collecting ducts, where determines a water reabsorbition through the synthesis and insertion in the luminal membrane of the water channel aquaporina-2 (AQP2) (16).
According to antidiuretic action of V2 receptor, since the 80's a large number of vasopressin antagonists has been investigated to treat hyponatremia. Because of limits linked to their peptide structure, the first peptide vasopressin antagonists were abandoned in favor of nonpeptide vasopressin antagonists, also known as vaptans.  (21). (TABLE II).
Until now two vaptans have been released for clinic use: conivaptan, as an intravenous preparation, and tolvaptan, as an oral tablet.
Conivaptan (Vaprisol®) was the first medication of this class to be approved by the FDA in 2005 for the treatment of hyponatremia in SIADH, hypothyroidism, pulmonary disorders and adrenal insufficiency in hospitalized patients (22) and two years later, in 2007, also for hypervolemic hyponatremia in hospitalized patients (23). The loading dose is 20 mg i.v. over 30 min and the maintenance dose is 20-40 mg i.v. for continuous infusion over 24h up to 96h. Differently from all the other vaptans, which are selective V2-receptor antagonists, conivaptan acts like a V1a-receptor and V2-receptor antagonist. This singularity could be investigated in a randomized trial to show if conivaptan is better than other vaptans in treating hyponatremic patients with CHF thanks to its cardiovascular action (V1a-receptor blockage causes reduction of vascular peripheral resistance and inhibits unfavorable myocardial remodeling). It is metabolized by CYP3A4.

SEARCH STRATEGY
We searched CENTRAL (The Cochrane Central Register of Controlled Trials) and PubMed databases from January 2000 to January 2012. We searched for "vasopressin receptor antagonists" AND "hyponatremia". In PubMed we applied filter for "Randomized Clinical Trial" and "Controlled Clinical Trial". No language restrictions were imposed. According to these criteria 17 trials are described in this review.
In table III (Results) these studies, sorted in chronological order, are described and commented in a systematic manner, according to a scheme that shows references; the typology of study; the vaptan used, the population enrolled and size of the two groups (drug versus placebo); the pharmacological intervention and the primary and secondary outcomes (when provided); results; observations.  The study, with a large number of patients and a long-term followup, shows that tolvaptan has no effect on longterm mortality or heart failurerelated morbidity; but it also shows that tolvaptan is the first drug ever evaluated in patients hospitalized for worsening HF for which combination of short-term symptomatic  A normal s [Na⁺ ] or an increase from baseline ≥ 6 mEq/L was significantly higher among patients given conivaptan 40 and 80 mg/die (67% and 88%, respectively) than placebo (20%; P < 0.001).
-Not evaluated the effects of other drugs allowed. c) frequency of paracentesis The frequency of paracentesis was decreased significantly (n all satavaptan groups vs placebo (p<0.05).
Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with satavaptan.
The trial included patients with or without hyponatraemia, and normal to mildly abnormal renal function.

IV. DISCUSSION
The analysis of the mentioned trials shows that nonpeptide vasopressin antagonists are safe and effective drugs in the short-term correction of hyponatremia in both the states of hypervolemia (liver cirrhosis and heart failure) and euvolemia (SIADH).
Certainly vaptans have a number of limitations. First of all, trials presented a percentage of 10-20% of patients who do not respond to treatment. The reason for this phenomenon has not yet been studied well. This can be partly attributed to altered pharmacokinetics (altered volume of distribution in oedematous states and water ingestion), in part to polymorphisms and mutations in the vasopressin receptors (43,44). On the other hand, vaptans may be associated with rapid correction of sodium values (> 12 h mEq/l/24) with potential risk of pontine myelinolysis, although the literature has not reported any cases of this complication in patients treated with these drugs.
Clinical response to vaptans in terms of aquaresis and hyponatremia correction is not the same in all subsets of patients. Patients with SIADH are those that respond best, while those with liver cirrhosis worse. Probably in the state of hypervolemia (CHF, liver cirrhosis) proximal tubular reabsorption reduces the effect that vaptans cause in distal tubular ducts. Further studies are needed to clarify this point. So clinicians need to keep in mind that therapy with vaptans should be individualized for each patient.
All studies were short term. Only Soupart (31) and Aronson (40) studied the effectiveness of satavaptan for one year, in SIADH and CHF respectively, demonstrating the efficacy and good tolerability in long-term treatment.
There are no studies comparing the efficacy between vaptans and traditional treatment (diuretics, hypertonic saline, urea,…) or between two different vaptans. This last point is considerable because, whereas conivaptan and mozavaptan (used in Japan for the treatment of hyponatremia in paraneoplastic SIADH)also block the V1a receptors, they may have superior efficacy compared to satavaptan, tolvaptan and lixivaptan (which are selective V2-receptor antagonists) in patients with heart failure.
All vaptans induce thirst and this effect is very important for compliance to therapy. Without doubt, the thirst is explained by the increased plasma osmolality that they determine, but it may be also linked to a direct action on vasopressin receptors of "thirst" in hypothalamic neurons.
In recent years the use of vaptans for treatment of emergency hyponatremia (45) and for the control of serum sodium and intracranial hypertension in neurosurgical patients has been discussed (38,41). For the correction of emergency hyponatremia, hypertonic saline remains the treatment of choice, but it has been hypothesized that vaptans could at least be taken into account to give a slower correction of sodium rate than hypertonic saline and no risk of pulmonary edema (45). With regard to the treatment of cerebral edema and intracranial hypertension in neurosurgical patients, the current target is to keep the patient "salty and full", with careful monitoring and rapid intervention to keep within normal limits the plasma osmolality and serum sodium (as well as the optimization of respiratory and cardiovascular functions, in addition to sedation, to guaranty an adequate DO₂ /VO₂ ) through the consolidated use of mannitol, hypertonic saline, diuretics. To the best of our knowledge, there are still no conclusive studies on these two issues and we wait for results in the coming years.

V. CONCLUSIONS Università degli Studi di Salerno
Vaptans are safe and effective drugs in the short-term treatment of hyponatremia due to hypervolaemic edematous states (liver cirrhosis, heart failure) and euvolaemic states (SIADH). They are contraindicated in hypovolaemic hyponatremia. About superiority of one vaptan above the other and comparison between vaptans and conventional therapy, questions are still open.